[en] BACKGROUND: Risdiplam, an oral pre-messenger RNA splicing modifier, is an efficacious treatment for persons with symptomatic spinal muscular atrophy (SMA). The safety and efficacy of risdiplam in presymptomatic disease are unclear. METHODS: We conducted an open-label study of daily oral risdiplam (with the dose adjusted to 0.2 mg per kilogram of body weight) in infants 1 day (birth) to 42 days of age with genetically diagnosed SMA but without strongly suggestive clinical signs or symptoms. The primary outcome, assessed in infants with two SMN2 copies and a baseline ulnar compound muscle action potential (CMAP) amplitude of at least 1.5 mV, was the ability to sit without support at month 12. Natural history studies have shown that the majority of infants with two SMN2 copies who are untreated would have a severe SMA phenotype (type 1), would never sit independently, would receive permanent ventilation and feeding support, or would die by 13 months of age. Secondary outcomes that were assessed over a period of 24 months included survival, ventilatory support, motor milestones, the development of clinically manifested SMA, feeding, and growth. RESULTS: A total of 26 infants with two, three, or four or more copies of SMN2 were enrolled. After 12 months of treatment, 21 infants (81%) could sit unsupported for 30 seconds, 14 (54%) could stand alone, and 11 (42%) could walk alone. A total of 4 of 5 infants (80%; 95% confidence interval, 28 to 100) with two SMN2 copies and a baseline ulnar CMAP amplitude of at least 1.5 mV were able to sit without support for at least 5 seconds. Three infants were withdrawn from the study by a parent or caregiver after the month 12 visit. Of 23 infants who completed 24 months of treatment, all were alive without the use of permanent ventilation or feeding support. Over a period of 24 months, nine treatment-related adverse events were reported in 7 infants; none of these events were serious. CONCLUSIONS: Infants up to 6 weeks of age with genetically diagnosed SMA who were treated with risdiplam before the development of clinical signs or symptoms appeared to have better functional and survival outcomes at 12 and 24 months than untreated infants in natural history studies. Larger, controlled studies with longer follow-up are needed to further understand the relative efficacy and safety of presymptomatic treatment of SMA with risdiplam. (Funded by F. Hoffmann-La Roche; RAINBOWFISH ClinicalTrials.gov number, NCT03779334.).
Disciplines :
Pediatrics Neurology
Author, co-author :
Finkel, Richard S; Center for Experimental Neurotherapeutics, Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN.
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; MDUK (Muscular Dystrophy UK) Oxford Neuromuscular Centre and NIHR (National Institute for Health and Care Research) Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
Vlodavets, Dmitry; Russian Children Neuromuscular Center, Veltischev Clinical Pediatrics and Pediatric Surgery Research Institute of Pirogov Russian National Research Medical University, Moscow.
Zanoteli, Edmar; Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo.
Mazurkiewicz-Bełdzińska, Maria; Department of Developmental Neurology, Chair of Neurology, Medical University of Gdańsk, Gdańsk, Poland.
Jong, Yuh-Jyh; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. ; Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. ; Translational Research Center of Neuromuscular Diseases, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. ; Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ; Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
Navas-Nazario, Aledie; Division of Pulmonology, Nemours Children's Health Orlando, Orlando, FL.
Al-Muhaizea, Mohammad; Neuroscience Center, King Faisal Specialist Hospital and Research Center-Riyadh, Riyadh, Saudi Arabia.
Araujo, Alexandra P Q C; Department of Pediatrics, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro.
Nelson, Leslie; Department of Physical Therapy, University of Texas Southwestern Medical Center, Dallas.
Wang, Yi; Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.
Jaber, Birgit; Pharma Development Safety, F. Hoffmann-La Roche, Basel, Switzerland.
Gorni, Ksenija; Product Development Medical Affairs, Neuroscience and Rare Disease, F. Hoffmann-La Roche, Basel, Switzerland.
Kletzl, Heidemarie; Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Palfreeman, Laura; Roche Products, Welwyn Garden City, United Kingdom.
Rabbia, Michael; Genentech, South San Francisco, CA.
Summers, Dave; Roche Products, Welwyn Garden City, United Kingdom.
Gaki, Eleni; Roche Products, Welwyn Garden City, United Kingdom.
Wagner, Kathryn R; Pharma Development Neurology, F. Hoffmann-La Roche, Basel, Switzerland.
Fontoura, Paulo; Product Development Medical Affairs, Neuroscience and Rare Disease, F. Hoffmann-La Roche, Basel, Switzerland.
Farrar, Michelle A; Department of Neurology, Sydney Children's Hospital Network, Sydney. ; Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW (University of New South Wales) Medicine, UNSW Sydney, Sydney.
Bertini, Enrico; Research Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Research Hospital IRCCS, Rome.
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